PROJECT ABSTRACT Osteoarthritis (OA) is a major cause of disability throughout the world, and prevalence of OA increases with age. With an aging population, the socioeconomic burden associated with OA is expected to increase over the coming years. The hallmark of this disease is a slow, progressive cartilage erosion driven in part by inflammation from an activated synovium (the tissue that surrounds the joint). Chondrocytes (the cells in cartilage) lose their capacity to maintain a healthy tissue as they become diseased. Macrophages (activated cells in the synovium) contribute to the chondrocyte phenotype shift and subsequent cartilage degradation through the secretion of pro-inflammatory molecules. Currently, there are no effective disease modifying treatments to intervene in this degradative cascade. The ultimate goal of this work is to develop a disease modifying intra- articular (IA) injection treatment which targets diseased chondrocytes and macrophages with one simple approach ? by shifting the cell membrane potential (Vmem) to a more positive (depolarized) state. Vmem depolarization can be achieved with a variety of methods, the easiest of which is through simply increasing the extracellular potassium concentration. However, in order to implement depolarization strategies into a disease modifying IA injection, we first need to demonstrate a proof-of-concept (i.e. that we can return activated, diseased cells to an unactivated state via depolarization) and determine the length, intensity, duration, and specificity of Vmem depolarization treatments. As such, we propose the following two Specific Aims: Aim 1: Establish the ability of Vmem depolarization to transition activated, cartilage explants and pro- inflammatory macrophages to a more normal, unactivated phenotype. Aim 2: Determine the length, intensity, duration, and specificity of Vmem depolarization treatments appropriate to IA injection approaches.